Bicyclic thiazole derivatives



United States Patent Qfiiee "2,933,497 Patented Apr. 19, 1960 BICYCLIC THIAZOLE DERIVATIVES Raymond M. Dodson, Park Ridge, 111., assignor to G. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Application January 29, 1958 Serial No. 711,810

9 Claims. (Cl. 260-251) This invention relates to bicyclic thiazole derivatives having the formula sired, by hydrolysis. The process may be represented as follows wherein R and n have the meanings as aforesaid Suitable l-cyanoalkanol arylsulfonic acid esters are those which contain the structure wherein at least one hydrogen is present on the carbon in the a-position relative to the cyano radical and include l-cyano-phenylalkyl benzenesulfonates such as a-cyanobenzyl benzenesulfonate and nuclearly halogenated derivatives thereof; l-cyano-Z-phenylethyl benzenesulfonate, lcyano-3-phenylpropyl benzenesulfonate and nuclearly halogenated derivatives thereof; alkyl benzensulfonates such as cyano-(cyclohexyDmethyl benzenesulfonate, l-cyano-3-cyclohexylpropyl benzenesulfonate and the like.

Suitable cyclic thiourea reactants include 2-imidazoli dinethione and trimethylene thiourea.

The condensation is carried out preferably at moderate temperatures, such as about room temperature to about 100", with the use of a metal iodide such as sodium iodide, potassium iodide, calcium iodide, magnesium iodide and the like, which, however, can be omitted in the case of in a-relation to the ester group.

Suitable solvents for the reaction are preferably nonhydroxylated solvents such as acetone, methyl ethyl ketone, dioxane and the like.

Hydrolysis of the 3-imino radical by heating with water 01 with aqueous acid, followed by neutralization and sepl-cyano-(cyclohexyl) aration of the product yields the corresponding 3-oxo analogs.

The condensation of the cyano-[(substituted)-alkyl] benzenesulfonate with the cyclic thiourea reactant yields;

the reaction, product in the form of a salt. The free base is obtained therefrom by treating the salt in aqueous solution with a base such as sodium hydroxide or ammonia, filtering or extracting with a solvent, e.g. methylene dichloride, and collecting the product.

For purposes of this invention the free bases and their pharmaceutically acceptable acid addition salts are equiv Any desired such salts are prepared readily from. the free base by dissolving the latter in an alcohol such as isopropanol and adding thereto an alcoholic solutionalent.

of the appropriate acid and recovering the product. Suitable acids for this purpose include the halogen acids such;

by weight and parts by volume which bear the same relation one to the other as kilograms to liters. tures are expressed in degrees centigrade.

Example 1 A suspension of 27.3 parts by weight of u-cyanobenzyl benzenesulfonate, 10.2 parts of weight of 2-imidazolidinethione and parts by volume of acetone is warmed to bring about complete solution, and is then allowed to stand at about 250 C. for 16 hours.

it is then allowed to stand until separation of an insoluble product appears complete. a filter; an additional quantity of the crude product is obtained by dilution of the filtrate with a large volume of water. The combined crude product is recrystallized from ethanol to afford the benzenesulfonic acid salt of 2- phenyl 3 imino 2,3,5,6 tetrahydroimidazo [2.1 b]

thiazole melting with decomposition at about ZZZ-224 C. v

The structural formula of the free base is N NH Example 2 A suspension of 27.3 parts by weight of u-cyanobenzyl :benzenesulfonate, 10.2 parts by weight of Z-imidazolidinethione and 80 parts by volume of acetone is warmed to bring about complete solution, and is then allowed to stand at about 25 C. for 16 hours. The mixture is diluted with approximately three volumes of water, allowed to stand for an additional 30 minutes, and filtered. The filtrate, chilled to about 0l0 C., is made basic with aqueous ammonia and then, with cooling and stirring,

acidified with acetic acid. After an additional 30 min-- utes, the insoluble product is collected on a filter, washed 1 with water and dried. The product thus obtained is the benzenesulfonic add salt of 2-phenyl-3-imino-2,3,5,6- tetrahydroimidazo[2.l-blthiazole, which is the same compound as that obtained by the procedure of Example 1. This preparation melts with decomposition at 1 about 226-229." C.

In addition, they I potentiate the sleeping time caused by barbiturates.

The invention is described in greater detail in the ex-. amples below which are presented by way of illustration and not of limitation. Quantities are expressed in parts Tempera- The mixture is diluted with water until a persistent turbidity results, and

This product is collected on apes-.497

benzenesulfonic acid salt of 2-phenyl-3-imino-2,3,5,6

tetrahydroimidazo[2.l-blthiazole in a small quantity of cold water is rendered basic with aqueous ammonia and then, 'after the addition of ice, made slightly acidic with acetic acid. About 4 parts by weight of solid produetis' collectedon afilter and washed with water. This product is dried and then suspended in 40 parts'b'y volume of methanol. A solution of hydrogen chloride in isopropyl alcohol, having-a concentration of about 0.24 gram of hydrogen chloride per milliliter and containing a total of 1.48 parts by weight of hydroge'nchloride, is-added, andthe mixture is stirred for one hour and then-allowed to stand for 24 hours. Ether (80 parts by volume) is added,'an'd the-product is collected on a filter and washed with ether. This compound is 2-phenyl-3-imino 2,3, 5,6- tetrahydroimidazo[2.1-blthiazole dihydrochloride. It melts with decomposition at about ZZZ-225 C.

Example 4 A mixture of 8. parts by weight of the'benzenesul'fonic acid salt of 2-phenyl-'3-imino-2,3,5,6-tetrahydroimidazo- [2.l-blthiazole, 100 parts by volume of water and 65 parts 'by volume of concentrated hydrochloric acid isheated at about 90-100 C. for 2 hours. The cooled reaction'mixture is filtered from an insoluble residue, and the filtrate is made basic with 90 parts by volume of concentrated aqueous ammonia. Upon neutralization with acetic acid, a precipitate 'forms. "This product is collected on'a filter and washed with water. It'is soluble 'in dilute aqueous ammonia, in dilute'hydrochloric acid, "and in hot water. Purification by recrystallization from water affords 2-phenyl-3-oxo2,3,5,6-tetrahydroimidazo[2.1-b]thiazole melting at about 139.5-1'405 C. The structural formula is "-The hydrochloride, prepared by treatment withhyd'rogen chloride in isopropyl alcohol followed by recrystallization from methanol, melts with decomposition at about 232-234 C.

.Example .5

Amixture of.10.26 parts by weight of a-cyano-2,4dichlorobenzyl benzenesulfonate, 3.06 parts. by weight ;of Z-imidaZolidinethione and 45 parts by volume of acetone isheated in order to promotesolution of thereactants and initiate separation of the insoluble reaction product. The mixture is then allowed to stand at about 25 C. for 18 hours, after which the insoluble product is collected on a filter and Washed with acetone. 7 The product thus obtained melts at about 199-20l C. and is the benzenesulfonic acid salt of 2-(2,4-dichlorophenyl)-3-imino- 2,3,5,6-tetrahydroimidazo[2.1-blthiazole. Upon recrystallization from a mixture of methanol and ether, the melting point is about 202-203 C. The structural formula "of .thefree base is or N s 'N NE A mixture is prepared from 5 parts by weight of'the benzenesulfonic acid salt as described immediately hereinabove, parts by volume of 'water and parts by volume of concentrated hydrochloric acid. When the reactants are brought together, there occurs partial solution followed by the separation of a precipitate. mixture isallowed to stand for 30 minutes vwithextemal cooling in an :ice bath, following which the insoluble product is collected on a filter and washed -withether. '1

dichlorophenyl) 3 imino 2,3,5,6-tetrahydroimidazo- For purification it is resuspended in acetone and again collected on a filter. The compound thus obtained is 2 (2,4 dichlorophenyl)-3-imino-2,3,5,6-tetrahydroimidazo [2.1-b1thiazole hydrochloride which melts to a viscous melt at about 161l62 C.

7 Example 6 A quantity of the-benzenesulfonic acid salt of 2- (2,4-

[2.1-blthiazoleis covered with an'excess of concentrated aqueous ammonia and stirred. After aboutfive'minutes a white, solid product is collected on a filter and washed with water. .The wetfilter cake is suspended in a small quantity of water, and concentrated hydrochloric acid is added in small portions until the mixture is distinctly acidic and a yellow solution results This solution is rapidly filtered from a small amount of insoluble residue, and the filtrate is allowed .to stand. A white, insoluble product separates within about one hour; Ether is added to facilitate filtration, and the insoluble product is collected on a filter and washed with additional quantitiesof ether.' The product thus obtained is 2-(2,4-dichlorophenyl) 3 oxo- 2,3,5,6-tetrahydroimidazo[2.1b]thi azole hydrochloride which melts'with decomposition at about 242245 C.,' after prior softening. The structural formula of the free base is 7 Example 7 A mixture of 15 parts by weight of a-cyanO-B,"4 dii the reactants. The mixture is then maintained at about 25 C. for 20 hours, following which it is concentrated to about one-half of its original volume by vaporization of acetone. Some impure material is precipitated by dilution with anhydrous ether and removed by filtration. The filtrate is brought to dryness by evaporation of the solvents. Theresidue thus obtained is suspendedin an excess of aqueous ammonia, and the mixture is extracted with ether. The ethereal solution is washed with water, rendered anhydrous over sodium sulfate, and filtered. When the ethereal filtrate is treated with hydrogen chloride in isopropyl alcohol, an insoluble product separates. This product is collected, washed with ether, andsubjected to furtherpurification by trituration with acetone.

The compound is 2- (3,4-dichlorophenyl)-3-oxo-2,3,5,6-

tetrahydroimidazo[2.1-blthiazole hydrochloride which melts with decomposition at about 246-247 C. after prior softening. A more highly purified sample can be prepared by triturating this product with water, collecting it again and washing it with ether. The'structural formula of the free base is Example 8 To -2s.2' parts by weight of o-'chlorobenzaldehyde,-'contemperature of the mixturedoes not exceed about' 35" 0., and preferably does not exceed room temperature.

An additional 20 parts by volume ofwate'r is addedf'and theLmixtnre-is stirred for 3 'rn'ore hours at about 05 (3.

The oily product is separated from the aqueous phase and dissolved in a mixture of 32 parts by volume of acetone, 32 parts by volume of ethanol and parts by volume of ether. A small quantity of insoluble residue is removed by filtration, and the filtrate is stirred with 60 parts by weight of ice until precipitation of the oily prodnet is complete. The oily product is separated and rendered anhydrous by filtering it through sodium sulfate. The product obtained amounts to about 70 parts by weight, and is a-cyano-2-chlorobenzyl benzenesulfonate containing a small amount of solvents. It is suitable for use in the following operation without further purification.

A mixture of the 70 parts by weight of crude a-cyano- 2-chlorobenzyl benzenesulfonate, as obtained immediately hereinabove, 20.4 parts by weight of Z-imidiazolidinethione and 80' parts by volume of acetone is heated under reflux until substantially complete solution of the reactants is achieved. The mixture is then maintained at about C. for 18 hours. Unreacted Z-imidazolidinethione which can be present is removed by filtration. The filtrate is diluted with water in order to precipitate an oily material. This mixture is refrigerated for 4 hours and washed with ether. The separated aqueous phase is made basic with concentrated aqueous ammonia and extracted with ether. This ethereal extract is dried over 31 N s Ul A N 0 Example 9 A slurry of 94 parts by weight of sodium cyanide in 100 parts by volume of water is added to a solution of 67 parts by weight of 3-cyclohexylpropionaldehyde and 86 parts by weight of benzenesulfonyl chloride which has been chilled to 0 C. Following the addition, the temperature rises to 35 C. The thick syrupy mixture is stirred and cooled until it solidifies. The solid is broken up and washed with 1500 parts by volume of water and recrystallized from alcohol-water to yield 1- cyano-3-cyclohexylpropyl benzenesulfonate, melting point 33.534 C.

A mixture of 7.7 parts by weight of 1-cyano-3-cyclohexylpropyl benzenesulfonate, 2.9 parts by weight of trimethylenethiourea and 3.75 parts by weight of sodium iodide in parts by volume of acetone is refluxed for one-half hour. The mixture is filtered hot to remove sodium benzenesulfonate and after cooling, 2-cyclohexylethyl 3 imino 2,3,6,7 tetrahydro-S-thiazolo[32a]- pyrimidine hydroiodide crystallizes. The solid is recovered and recrystallized from methanol-water; melting point l54157 C.; infrared maxima at 6.08, 6.22, 6.59, 6.95, 7.32, 7.60, 7.69 and 8.63 microns. The compound has the formula v N S CHzCHr- H2 N NH H: 1

sodium sulfate, filtered, chilled and treated with a slight Example 10 by weight of sodium cyanide and 55 parts by volume of water is added in 4 portions. After stirring for an additional hour, the mixture solidifies. The solid is broken up, filtered OE and washed with 1000 parts by volume of water to give 1-cyano-3-phenylpropyl benzenesulfonate.

A mixture of 28.9 parts by weight of I-cyano S-phenylpropyl benzenesulfonate, parts by volume of acetone and 15 parts by weight of sodium iodide is allowed to stand overnight. The solid precipitate is separated by filtration and washed with 75 parts by volume of acetone. To the filtrate, 5.8 parts by weight of trimethylenethiourea is added and the resulting solution is refluxed for 4 hours and filtered hot. The filtrate is concentrated to 50 parts by volume, cooled and allowed to stand. The precipitate which forms is separated by filtration and recrystallized from a mixture of methanol and methyl ethyl ketone to yield 2-phenylethyl-3-imino-2,3,6,7-tetra- N s i W IomomQrrr N NH Example 11 A solution of 18.4 parts by weight of l-cyano-3-cyclohexylpropyl benzenesulfonate, parts by volume of acetone and 9 parts by weight of sodium iodide is allowed to stand for 24 hours after which the mixture is filtered and the solid which separates is washed with 25 parts by volume of acetone. To the filtrate is added'6.1 par-ts by weight of 2-imidazolidinethione; the mixture is heated under reflux for 4 hours, cooled and filtered. The solid is washed with a little acetone which is added to the filtrate. The filtrate is concentrated, the solid which precipitates is recovered, washed with 10 parts by volume of water, triturated with 10 parts by volume of acetone and washed with ether to yield 2-cyclohexylethyl-Zv-imino- 2,3,5,6-tetrahydroimidazo[2.1 blthiazole hydroiodide which melts at ZOO-202 C. and exhibits infrared absorption maxima at 5.92, 6.05, 6.21, 6.88, 7.41, 8.13 and 8.27 microns and has the formula 11 H, n, N s I Y onion; Him

Ha Ha N -NH One part by weight of 2-cyclohexylethyl-3-imino- 2,3,5,6-tetrahydroimidazo [2.1-b] thiazole hydroiodide is dissolved in water containing a little methanol and an excess of aqueous ammonia added. A precipitate of the free base forms which is recovered and, after air drying, melts at 93.5-96" C. a solution of hydrogen chloride in methanol is added. A precipitate is formed immediately which is the dihydrochloride of 2-cyclohexylethyl-3-imino-2,3,5,6-tetrahydroimidazo-[2.1-blthiazole; melting point 158-160 C.

Example 12 A solution of 2 parts by weight of 2-cyclohexylethyl 3 imino 2,3,5,6 tetrahydroimidazo[2.1 b] thiazole hydroiodide in the minimum quantity of methanol is diluted with concentrated aqueous ammonia until a precipitate is obtained. The solid precipitate is recovered and mixed with a methanolic solution of hydrogen chloride. A new solid begins forming before all of the free base has dissolved. The mixture is allowed to stand for one half hour. Tl eprecipitate which tormsis recoil;

It is dissolved in methanol to which- N s Y Iomom'Qmnor 7 H2 H2 A mixture of 0.1 part by weight of 2-cyclohexylethyl- 3-imino-l2,3,5,6-tetrahydroirnidazo [2.1-b1thiazole dihydrochloride and three parts by volume of Water is heated for one-half hour. Concentrated ammonia is added to the clear solution. The aqueous layer is decanted from the oily layer which is dissolved in ether, diluted with petroleum ether and filtered. The filtrate is concentrated in vacuo to yield 2-c ciohexy1ethy1-3-oxo-2,3,5,6 tetrahyr droimidazo[2.1-b1thiazole as an oil which exhibits in frared maxima at 3.36, 3.45, 5.92, 6.12, 6.88, 7.15, 7.43 and 8.05 microns.

Example 13 A solution of 28.9 parts by Weight of l-cyano-3-phenylpropyl benzenesulfonate, 75 parts by volume of acetone and 15 parts by weight of sodium iodide is allowed to stand overnight. The mixture is filtered, the solid Washed with 75 parts by volume of acetone and the filtrates combined. To this solution is added 3.9 parts by weight of Z-imidazolidinethione and the resulting solution refluxed for 4 hours. The reaction mixture is filtered and the filtrate concentrated in vacuo to 25 parts by volume. The solid which forms is recovered and is 2- phenylethyl- 3-imino-2,3,5,6-tetrahydroimidazo [2. l-b] thiazole hydroiodide which exhibits absorption maxima in the vinirared at 5.93, 6. 04,;621, 6.67,v 6.85, 7.41 7.68, 8.05 and 8.29 microns. The product has the formula Substitution of an equivalent quantity of 1-cyano14- phenylbutyl 'benzenesulfonate (prepared from phenylbutyralo'ehyde according to the procedures of Example 9) for the 1-cyano-3-phenylpropyl benzenesulfonate and otherwise following the above procedure. yields 2-phenyl-. propyl 3 imino 2,3,5,6 tetrahydroimidazo[2.1-blthiazole hydroiodide.

Example 14 A mixture of 10 parts by weight of 2-phenylethyl-3- mime- 2,3,6,7 tetrahydro 5 thiazolo[3.2-a]pyrimihas the formula ,N .s i

\ CHzCHr- N n. .O V

Example 1 5 V A mixture of parts by weight of 2-pheny1cthy1-3- imino 2,3,5,6 -'tetrahydroim-idazoEZ.l-b]thiazole hydroiodicle and 75 parts by volume of water is heated on the steam bath for several hours. 7 After standing overnight,

the aqueous layer is decanted, the residue recovered, washed with waterand triturated with methanol. The crystalline residue is recovered to yield 2-phenylethyl-3- oxo-Z,3,5,6-tetrahydroimidazo [2..1-b1thiazole hydroiodide exhibiting absorption maxima in the infrared at 5.75, 5.95, 6.2, 6.7, 6.85, 7.2 and 7.4 microns. The product has the formula 7 Example 16 A slurry of 94 parts by weight of sodium cyanide in 100 parts by volume of water is added to a solution of 77 parts by weight of 4-cyclohexylbutyraldehyde and 88 parts by weight of benzenesulfonyl chloride which has been chilled to 0 C. Following the addition, the temperature rises to about 35 C. and the thick syrupy mixture is stirred and cooled until it solidifies. The solid is. broken up and washed with 1500 parts by volume of Water and crystallized from alcohol Water to yield 1-' cyano-4-cyclohexylbutyl *benzenesulfonate.

A mixture of 8.0 parts of weight of 1-cyano-4-cyclohexylbutyl benzenesulfonate, 2.9 parts by weight of trimethylenethiourea and 3.75 parts by weight of sodium iodide in parts by volume of acetone is refluxed for one-half hour. The mixture is filtered hot to remove sodium benzenesulfonate and, after cooling, 2-cyclohex-ylpropyl 3 imino 2,3,6,7 tetrahydro5,-thiazolol'3.2-a]- H Hz N S I H2 Example 17 A mixture of 53 parts by weight of 2,4-dibromobenzaldehyde and 35 parts by weight of benzenesulfonyl chloride is heated on a steam bath, then stirred and cooled to 0 C. To the mixture is added a solution of 11 parts by weight of sodium cyanide in 30 parts by volume of water. after which time the oily organic layer is separated and 'washed repeatedly with water to yield crude u-cyano-ZA- dibromobenzyl benzenesulfonate- A mixture of '12 parts by weight of. a-cyano-ZA-dibr'omobenzyl benzenesulfonate, 3.1 parts by weight of Z-irnidazolidinethione and 45 parts by volumeofacetone is heated in order to promote solution of the reactants and initiate separation of the insoluble reaction product.

The mixture is then allowed to stand at about 25 C.

for 18 hours, after which the insoluble product is col-' lected on a filter and washed with acetone. The material is recrystallized from a mixture of methanol and ether to yield the benzenesulfonic acid salt of 2-(2,4-dibromophenyl) 3 imino 2,3,5,6- tetrahydroimidazo[ 2.1-b]- thiazole, the free base of which has the formula a N s N NE,

, Example 18 A mixture of 31 parts by weight of 4-chlorophenyl- 'acetaldehyde and 35 parts by weight of benzenesulfonyl and 9.5 microns Stirring is continued for 3 hours at-O-S C..

continued for 3 hours at -5 C. after which time the oily organic layer is separated and washed repeatedly with water to yield a-cyano-4-chlorophenylethyl benzenefulfonate. A solution of 10 parts by weight of acyano-4-chlorophenylethyl benzenesulfonate, 5 parts by Weight of sodium iodide and 50 parts by volume of acetone is allowed to stand at room temperature for 24 hours, filtered and the solid which separates washed with parts by volume of acetone. To the combined filtrate and washing is added 3.1 parts by Weight of 2'imiclazolidinethione. The resulting mixture is heated under reflux for 4 hours, cooled and filtered. The acetone filtrate is concentrated and the solid which precipitates is recovered, washed with water, triturated with acetone and washed with ether to yield the hydroiodide of 2(4-chlorobenzyl)-3-imino-2,3,5,6-tetrahydroirnidazo [2.1-blthiazole of the formula N S y .HI

N NE

What is claimed is: 1. A compound of the formula Hz) "LL:

wherein n is selected from the group of numerals consisting of 1 and 2, R is selected from the group of radicals consisting of phenyl, chlorinated phenyl, phenyl (lower)alkyl, chlorinated phenyl(lower)alkyl and cyclohexyl(lower)alkyl, and X is selected from the group of radicals consisting of imino and oxo.

2. 2 phenyl 3 imino 2,3,5,6 tetrahydroimidazo- [2.1-blthiazole.

3; 2 phenyl 3 oxo 2,3,5,6 tetrahydroimidazo- [2.1-blthiazole.

4. 2-(2,4-dichlorophenyl) 3 imino 2,3,5,6-tetrahydroimidazo[2.1-blthiazole.

5. 2-(2,4-dichlorophenyl)-3-oxo 2,3,5,6 tetrahydroirnidazo[2.1-b] thiazole.

6. 2-cyclohexylethyl-3-imino 2,3,6,7 tetrahydro-S- thiazolo[3.2-a]pyrimidine.

7. 2 phenylethyl 3 imino 2,3,6,7 tetrahydro-S- thiazolo[3.2-alpyrirnidine.

8. 2-cyclohexy1ethyl 3 oxo 2,3,5,6 tetrahydroimidazo [2.1-blthiazole.

9. Z-cyclohexylethyl 3 imino 2,3,5,6 tetrahydroimidazo[2.1-b]thiazole.

References Cited in the file of this patent UNITED STATES PATENTS 2,527,265 Kendall et a1 Oct. 24, 1950 UNITED STATES IIATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,93%497 April 19 1960 Column 2, line 36, vfor "parts of weight" read parts by weight column 5 line l5 for "2-imidiazolidine=-" read 2imidaz0lidine same column 5 lines 39 to 44 the formula should appear as shown below instead of as in the patent:

(SEAL) Attest:

KARL H. AXLINE ROBERT C, WATSON v Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA 